Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes

Suraj Kannan, Matthew Miyamoto, Renjun Zhu, Michaela Lynott, Jason Guo, Elaine Zhelan Chen, Alexandre R. Colas, Brian Leei Lin, Chulan Kwon

Research output: Contribution to journalArticlepeer-review

Abstract

A limitation in the application of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) is the failure of these cells to achieve full functional maturity. The mechanisms by which directed differentiation differs from endogenous development, leading to consequent PSC-CM maturation arrest, remain unclear. Here, we generate a single-cell RNA sequencing (scRNA-seq) reference of mouse in vivo CM maturation with extensive sampling of previously difficult-to-isolate perinatal time periods. We subsequently generate isogenic embryonic stem cells to create an in vitro scRNA-seq reference of PSC-CM-directed differentiation. Through trajectory reconstruction, we identify an endogenous perinatal maturation program that is poorly recapitulated in vitro. By comparison with published human datasets, we identify a network of nine transcription factors (TFs) whose targets are consistently dysregulated in PSC-CMs across species. Notably, these TFs are only partially activated in common ex vivo approaches to engineer PSC-CM maturation. Our study can be leveraged toward improving the clinical viability of PSC-CMs.

Original languageEnglish (US)
Article number112330
JournalCell Reports
Volume42
Issue number4
DOIs
StatePublished - Apr 25 2023

Keywords

  • CP: Stem cell research
  • cardiomyocyte
  • maturation
  • single-cell RNA sequencing
  • stem cells
  • tissue engineering

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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